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Results for “Drug Collateral Sensitivity”

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At least 217 records · Page 12Linked to original sources

PubMed1983

Multidrug-resistance phenotype in Chinese hamster ovary cells.

Multidrug resistance is a complex pleiotropic phenotype of cross-resistance and collateral sensitivity to unrelated compounds observed in many mammalian cell mutants selected for resistance to single agents. In Chinese hamster ovary cells, colchicine-resistant mutants expressing this phenotype have been characterized extensively. Such mutants arise apparently from a single genetic event, and the basis of this phenotype appears to be localized at the membrane level, resulting in altered drug permeability. Expression of a 170,000-dalton surface glycoprotein (P-glycoprotein) has been identified to correlate with the multidrug-resistance phenotype. Selection of a second mutation in colchicine-resistant mutants, for resistance to phytohemagglutinin, results in an alteration of the carbohydrate moiety in P-glycoprotein and other surface components. This mutation does not noticeably affect the multi-drug-resistance phenotype. The altered permeability of mutant cells to drugs, however, can be modulated by nonionic detergents or metabolic inhibitors. These findings are consistent with a molecular mechanism of multidrug resistance whereby the pleiotropic response of the cell is mediated by an overexpression of a cell-surface protein, the P-glycoprotein.

Animals↗

PubMed1993

Modulation of multidrug resistance gene expression by dexamethasone in cultured hepatoma cells.

Considerable evidence has accumulated indicating that overexpression of P-glycoproteins encoded by the multidrug-resistance (mdr) genes is responsible for the development of collateral resistance to a number of structurally and functionally dissimilar cytotoxic compounds in animal cells. There are three mdr genes (mdr1, mdr2, and mdr3) in the mouse genome and two (MDR1 and MDR2) in the human genome; however, only two mouse genes (mdr1 and mdr3) and one human gene (MDR1) can confer multidrug resistance upon transfection into otherwise drug-sensitive cells. Using RNase protection assay we report here that the steady-state levels of mdr1 and mdr3 messenger RNA were elevated in mouse hepatoma cells treated with dexamethasone (Dex); whereas no induction of mdr2 gene was found. Western blot analyses using anti-mdr1 and anti-mdr3 antibodies revealed that the encoded proteins appeared to be increased, but at much reduced levels. The induction was time and Dex concentration dependent. Nuclear run-on experiments demonstrated that the induction was at least in part by transcriptional control. The induction apparently required new protein synthesis since no increases in mdr1 and mdr3 transcripts was found when cultured cells were simultaneously treated with Dex and cycloheximide. Neither mdr1 nor mdr3 gene was induced in the Dex-treated nonhepatoma cell lines, LMtk- and NIH3T3. Similarly, MDR1 messenger RNA levels were elevated in the Dex-treated human hepatoma line, HepG2, but not in the nonhepatoma, HeLa. This study demonstrated that the hormonal regulation of mdr gene expression is gene and cell type specific.

3T3 Cells↗

PubMed1979

Metabolism and effects of 5-(beta-D-ribofuranosyl)isocytosine in P815 cells.

5-(beta-D-Ribofuranosyl)isocytosine (psi l Cyd), a C-nucleoside, has been shown to be active against P815 leukemia in mice. In P815 cells treated with [2-14C]psi l Cyd, we have detected radioactivity in nucleotide fractions and in RNA and DNA. Degradation to nucleosides of the labeled triphosphate nucleotide fraction and of RNA showed that the radioactivity present was chromatographically identical to psi l Cyd. Half-saturation concentrations for the incorporation of [2-14C]psi l Cyd into the triphosphate nucleotide fraction and into RNA and DNA were 370, 280, and 94 microgram/ml, respectively, which were greater than 100-fold higher than those for tritiated cytidine. The incorporation of psi l Cyd was competitively inhibited by cytidine. Phosphorylation and incorporation of psi l Cyd into nucleic acids of P815 cells and of a P815 subline resistant to 1-beta-D-arabinofuranosylcytosine are about 2- to 20-fold higher than in P815 sublines resistant to psi l Cyd or to both 5-azacytidine and 1-beta-D-arabinofuranosylcytosine. These data suggest that the phosphorylation of psi l Cyd and possibly its incorporation into nucleic acids are essential for therapeutic activity in P815 leukemias. In vitro metabolic studies also suggest that psi l Cyd and 5-azacytidine are cross-resistant and that P815 cells resistant to psi l Cyd are collaterally sensitive to 1-beta-D-arabinofuranosylcytosine. These predictions were confirmed by therapeutic experiments carried out in mice bearing P815 leukemias.

Animals↗

PubMed1994

Characterization of a human bladder cancer cell line selected for resistance to mitomycin C.

This study describes characteristics of a human bladder cancer cell line J82/MMC that is 6-fold more resistant to mitomycin C (MMC) than the parental cells. The J82/MMC subline was isolated by repeated continuous exposures of the J82/WT cells to increasing concentrations of MMC. The J82/MMC cell line showed (1) collateral sensitivity to taxol, 5-FU and topoisomerase II inhibitors; and (2) cross-resistance to cisplatin, melphalan and MMC analogues BMY 25282 and BMY 25067. Levels of two key MMC activation enzymes, NADPH cytochrome P450 reductase and DT-diaphorase, were significantly lower in J82/MMC cells compared with J82/WT, suggesting that lower sensitivity of J82/MMC cells to MMC may result from deficient drug activation. Further support is indicated by: 1) reduction in the differential in toxicity between the 2 cell lines by BMY 25282; and 2) a higher effect of DT-diaphorase inhibitor dicumarol on the wild-type cells compared with J82/MMC. Although glutathione (GSH) levels did not differ in these cells, a small but significant increase in GSH transferase (GST) activity was noticed in J82/MMC cells. GST inhibitor ethacrynic acid significantly enhanced MMC cytotoxicity in the J82/MMC cell line. A small but significant increase in the level of anti-oxidative enzyme catalase, but not GSH peroxidase, was also observed in J82/MMC cell line compared with J82/WT. Thus, the possibility that relatively lower sensitivity of J82/MMC cells to MMC may result from reduced oxygen radical generation cannot be ruled out. MMC-induced DNA interstrand cross-linking was markedly lower in the J82/MMC cell line compared with J82/WT. Our results suggest that the MMC resistance in the J82/MMC cell line may be multifactorial.

Antineoplastic Agents↗

PubMed1995

Myocardial protection with calcium-channel blockers during ischaemia and reperfusion by PTCA.

The effects of calcium channel blockers on acute myocardial ischaemia have been evaluated over the past two decades. A number of experimental studies have demonstrated that calcium antagonists protect the myocardium when administered before or during PTCA. Intracoronary verapamil prior to the second inflation attenuates the severity of ischaemic ST-segment changes and anginal pain. Heart rate and blood pressure are not influenced by verapamil or placebo. Similarly, there are multiple clinical and biological data suggesting that intracoronary nifedipine, diltiazem or bepridil, and intracoronary or intravenous nicardipine might result in a reduced incidence of myocardial ischaemia during PTCA. The beneficial effect of these drugs can be explained by a direct cardioprotective effect or by an enhanced collateral flow and haemodynamic improvement. During early reperfusion in acute myocardial infarction (AMI) administration of calcium channel blockers or agents that inhibit calcium release from the sarcoplasmic reticulum can protect hearts from stunning and can decrease the no-reflow phenomenon. The most recent explanation relates this observation to decreased sensitivity of the myofibrils to calcium. Further clinical and experimental studies are necessary to clarify the protective role in reperfusion injury. To summarize, therefore, administration of calcium channel blockers can decrease ischaemia during elective PTCA and can reduce reperfusion injury during early PTCA in AMI.

Angioplasty, Balloon, Coronary↗

PubMed2002

Osteosarcoma cells, resistant to methotrexate due to nucleoside and nucleobase salvage, are sensitive to nucleoside analogs.

PURPOSE: To test a novel strategy for overcoming intrinsic resistance to methotrexate (MTX) in osteosarcoma (OS) due to nucleoside and nucleobase salvage (NS). METHODS: Four OS cell lines, found to be highly resistant to MTX, were tested to determine the dominant mechanism of resistance. Sensitivity to MTX was tested in the presence of dialyzed serum or the transport inhibitor dipyridamole (DP) to confirm the contribution of NS to MTX resistance. We then investigated whether increased NS activity could be exploited using cytotoxic nucleoside analogs. RESULTS: Like other cell types, OS cells are capable of circumventing inhibition of de novo nucleotide synthesis by relying on NS. MTX, at concentrations as high as 1 m M did not inhibit cell growth in culture medium supplemented with undialyzed serum. In contrast, when NS was inhibited by DP or in medium depleted of nucleosides and nucleobases, sensitivity to MTX was seen at nanomolar concentrations. In medium with dialyzed serum, thymidine and hypoxanthine provided dose-dependent protection from MTX toxicity at concentrations similar to those seen in human plasma. No evidence of other significant mechanisms of resistance were found. All four cell lines were sensitive to 3-day exposures to cytarabine (IC50 0.22 to 2.88 micro M) and vidarabine (IC50 0.09 to 0.95 micro M). CONCLUSIONS: Salvage of de novo nucleotide synthesis inhibition by extracellular thymidine and hypoxanthine, at physiologically relevant concentrations, contributes to resistance to MTX in OS. However, this same process may impart a collateral sensitivity to nucleoside analogs. These findings support clinical trials for patients with OS using nucleoside analogs, either alone or in combination.

Animals↗

PubMed1989

Differential effect of collaterally sensitive antimetabolites on P388 murine leukemia sensitive and resistant to adriamycin in vitro.

Experiments were carried out in vitro using DNA polymerase and ribonucleotide reductase inhibitors to investigate their cytotoxicity to P388 murine leukemia sensitive (P388/S) and resistant (P388/R) to adriamycin (ADR). DNA polymerase inhibitors such as cytosine arabinoside (ara-C) and aphidicolin elicited comparative inhibition of DNA biosynthesis in both parental and ADR-resistant tumor cells. However, ribonucleotide reductase inhibitors such as hydroxyurea (HU) and caracemide were collaterally more sensitive to P388/R cells. Inosine diglycolaldehyde (Inox) was ineffective in showing such a response. Pretreatment with HU significantly increased intracellular ADR levels and inhibition of RNA biosynthesis by ADR in P388/R cells while, in P388/S cells, sequential or concurrent treatment with HU did not enhance intracellular ADR levels. Mechanisms underlying such an effect, implications due to reduced intracellular ATP levels in drug-resistant cells, and the possible utility of using ribonucleotide reductase as a target in drug-resistant tumors for the therapeutic benefit are discussed.

Animals↗

PubMed2004

Establishment and some characteristics of epoxomicin (a proteasome inhibitor) resistant variants of the human squamous cell carcinoma cell line, A431.

A431 resistant variants to epoxomicin (EXM) were established, showing 4.0-6.7 times more resistance to EXM than parental A431P. Both variants demonstrated increased expression of the beta-subunit molecules of 26S proteasome with approximately 2.5 times increased activity. In variant cells, cyclin B and P34cdc2 were over-expressed, whereas P21WAF1 was expressed at a similar level to A431P. Because of the proteasome inhibitor acting as a G2/M blocker, results are to the advantage of resistant cells proliferating in the presence of an inhibitor under a severe environment. Variant cells showed increased expression of epidermal growth factor receptor (EGFR) and decreased expression of mRNA, but also slight accumulation of protein of c-Cbl, which is a negative regulator of EGFR possessing ubiquitin ligase activity to desensitize EGF signaling. UbcH7, acting intimately with c-Cbl, was decreased in level compared to A431P. These phenomena can be regarded as one of the causes of prevention of c-Cbl-mediated down-regulation of EGFR in variant cells, enabling them to live. The anti-apoptotic Bcl-2 mainly consisted of a phosphorylated form with resistance to proteasomal degradation, suggesting that Bcl-2 phosphorylation occurred independently of its apoptotic function. Variant cells showed resistance not only to EXM, but to the 5 proteasome inhibitors, while demonstrating collateral sensitivity to doxorubicin.

Apoptosis↗

PubMed1991

Establishment of a human leukemia subline resistant to the growth-inhibitory effect of 12-O-tetradecanoylphorbol 13-acetate (TPA) and showing non-P-glycoprotein-mediated multi-drug resistance.

We have previously reported that K562/ADM, a typical P-glycoprotein-mediated multi-drug-resistant cell line, is cross-resistant to the growth-inhibitory effect of 12-O-tetradecanoylphorbol 13-acetate (TPA) and non-TPA type tumor promoters. To elucidate the mechanism of cross-resistance to tumor promoters in K562/ADM, we have established a K562 subline resistant to TPA-induced growth inhibition by exposing K562 cells to N-methyl-N'-nitro-N-nitrosoguanidine for 24 hr followed by continuous exposure to TPA. A K562 subline resistant to the TPA-induced growth inhibition, termed K562/TPA, was selected by a limiting dilution technique. K562/TPA was more than 500-fold resistant to TPA compared with parental K562 cells. K562/TPA showed cross-resistance to etoposide, teniposide, adriamycin (ADM), vincristine, vindesine and 3-[(4-amino-2-methyl-5-pyrimidinyl)] methyl-1-(2-chloroethyl)-1-nitrosourea, but showed collateral sensitivity to cisplatin. Although K562/ADM was not cross-resistant to 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin (MX2), an anthracycline derivative, K562/TPA was cross-resistant to MX2. By Northern blot analysis, K562/TPA did not express MDR-1. Accumulation of ADM by K562/TPA was no lower than that of K562 although that of K562/ADM was 5-fold lower than K562. We examined the subcellular distribution of ADM by fluorescence microscopy. The fluorescence of ADM was located in the nucleus of K562 and mainly in the cytoplasm of K562/TPA and K562/ADM. The distribution of ADM in K562/TPA, however, was different from that in K562/ADM. These results suggested that K562/TPA had a non-P-glycoprotein-mediated multi-drug-resistance phenotype and that the mechanism of drug-resistance in this cell line might be explained by an alteration in the intracellular drug distribution.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1989

Activity of the pyrazoloacridines against multidrug-resistant tumor cells.

A series of 2-aminoalkyl-5-nitropyrazolo [3,4,5-kl]acridines (pyrazoloacridines) were tested in vitro against a panel of multidrug-resistant cell lines comprising Adriamycin-resistant P388 leukemia, B16 melanoma, and mammary adenocarcinoma 16c. This new class of anticancer agents, particularly the 9-substituted methoxy derivatives, exhibited significant activity against all of the lines tested. The degree of cross-resistance to these compounds ranged from zero to 8-fold in the 138-fold Adriamycin-resistant P388/ADR line and was greatly diminished in the B16/ADR and 16c/ADR lines. Selected pyrazoloacridines were subsequently tested in vivo against B16 and B16/ADR cells established as solid tumors from the tissue culture line and shown to retain a significant degree of Adriamycin resistance. Whereas the B16/ADR line exhibited 2 logs less net tumor-cell kill than the B16 parent in response to Adriamycin treatment, the resistant tumor was completely sensitive to the pyrazoloacridines tested and proved in some experiments to be collaterally sensitive. The favorable activity of the pyrazoloacridines against these Adriamycin-resistant tumor lines points to the potential efficacy of these compounds against multidrug-resistant tumors encountered clinically.

Acridines↗

PubMed1992

Megestrol acetate reverses multidrug resistance and interacts with P-glycoprotein.

We evaluated the multidrug resistance (MDR)-modulating effects of progesterone (PRG) and an orally active, structurally related compound, megestrol acetate (MA), in several MDR human cell lines. At 100 microM, both steroids inhibited the binding of a Vinca alkaloid photoaffinity analog to P-glycoprotein (P-gp) in MDR human neuroblastic SH-SY5Y/VCR cells [which show greater than 1500-fold resistance to vincristine (VCR) in the tetrazolium dye (MTT) assay]. However, 100 microM MA markedly enhanced the binding of [3H]-azidopine to P-gp in both SH-SY5Y/VCR cells and the MDR human epidermoid KB-GSV2 cell line (which displays 250-fold resistance to VCR in the MTT assay). PRG had little effect on the binding of [3H]-azidopine to P-gp. MA at low doses was more effective than PRG in sensitizing cells to VCR and enhancing their accumulation of [3H]-VCR. The highly resistant SH-SY5Y/VCR subline exhibited significant collateral sensitivity to both steroids. These data suggest that MA may be a clinically useful modulator of MDR.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Gemcitabine monotherapy in recurrent ovarian cancer: from the bench to the clinic.

Gemcitabine (2'2'-difluorodeoxycytidine [dFdC]) is a synthetic analog of deoxycytidine with two fluorine atoms at the 2' position of the carbohydrate. As a hydrophobic molecule, dFdC competes for intracellular access via membrane-associated nucleoside transporter proteins. Following intracellular transport, dFdC is phosphorylated sequentially by deoxycytidine kinase to gemcitabine triphosphate, which inhibits ribonucleotide metabolism, hinders DNA processing, and increases accumulation of intrastrand adducts and interstrand cross-links, thereby leading to a G1 block in the cell cycle. dFdC monotherapy has been extensively evaluated at doses of 800-1250 mg/m2. dFdC is generally well tolerated, with the most frequently occurring dose-limiting toxicities being hematologic, noncumulative, and easily managed by dose alteration. Several studies involving treatment of recurrent ovarian cancer patients with dFdC monotherapy, most of whom had platinum-resistant disease and/or prior exposure to paclitaxel, led to overall response rates of 14-22% and a median duration of response of 4.0-10.6 months. An additional one third of the participants experienced stable disease for an overall clinical benefit in approximately one half of the treated patients. Tumor cells with a multidrug resistance phenotype have increased sensitivity to dFdC (collateral sensitivity). As dFdC is unaffected by platinum resistance, and not susceptible to classic multidrug resistance, it could be particularly beneficial to administer following treatment with agents that induce multidrug resistance. Integration of dFdC with platinum and/or radiation should also be investigated.

Antimetabolites, Antineoplastic↗

PubMed1996

In vitro and in vivo characterisation of low-resistant mouse reticulosarcoma (M5076) sublines obtained after pulse and continuous exposure to cisplatin.

In order to simulate drug resistance observed in the clinic, two cisplatin-resistant cell lines were produced from a murine ovarian reticulosarcoma, M5076 (M5), by pulse (M5/CDDP) and continuous (M5/CDDPc) treatment with cis-diamminedichloroplatinum(II)(CDDP). These cell lines showed a similar stable low level of resistance (approximately 3-fold) to CDDP and cross-resistance to carboplatin, iproplatin and the new alkylating agent tallimustine, but not to L-PAM (L-phenylalanine mustard) and BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea). Collateral sensitivity to two inhibitors of topoisomerase II, VP16 (etoposide) and doxorubicin (Dox), but cross-resistance to the topoisomerase I inhibitor, camptothecin, were observed. The two cell lines were also sensitive to 5-fluorouracil. No increase in the level of glutathione or activity of glutathione S-transferase could be observed in resistant cells compared with the parental M5 cells. Total DNA platination immediately after treatment was similar in the parental and resistant cell lines. Repair of total DNA platination, measured after 24 h of recovery, was undetectable in M5 and M5/CDDP cells, but was 33% in M5/ CDDPc cells. Initial DNA-interstrand cross-links (DNA-ISC) were six times higher in M5 than in M5/CDDP cells, but 24 h after treatment, both lines had completely repaired this damage. M5/ CDDPc cells did not show formation of DNA-ISC at any time after treatment. The two resistant cell lines were tumorigenic when implanted in mice and resistant to CDDP treatment in vivo. The CDDP resistant tumours were not cross-resistant in vivo to L-PAM, BCNU and Dox, which had been active in vitro, nor to tallimustine, which had been cross-resistant in vitro. Mechanisms of resistance in M5/CDDP and M5-CDDPc seem to be based on a lower formation of DNA-ISC combined, for the latter cell line, with a higher repair capacity for total DNA platination.

Animals↗

PubMed1997

[Overview of the most frequent clinical manifestations of peripheral arterial occlusive disease in the elderly, its diagnosis and stage-related therapy].

The peripheral artery occlusive disease is a widely spread disease and its diagnosis, treatment options and consequences are frequently underestimated. Especially for the old patient, preservation of an extremity may mean mobility and quality of life. The increasing life expectancy and behaviour of prosperity including a lack of mobility are causing a rise in the frequence of atherosclerotic diseases. The prevalence of occlusive vascular diseases in patients between 55 to 64 years of age is currently 11% and is, therefore, a wide-spread disease. However, the socio-economic relevance of the occlusive vascular diseases is frequently underestimated. It causes both very high direct costs (treatment procedures, prostheses etc) as well as high indirect costs (permanent disability). Therefore, early diagnosis and treatment plays an important role in the avoidance of a progression of the disease. For an early diagnosis of the stage I of occlusive vascular diseases it makes sense to examine the vessels of patients at risk (i.e. diabetes mellitus, hypertension, hyperlipidemia, nicotine abuse, and overweight). Dopplerultra-sound and oscillometry are highly sensitive and specific diagnostic measures. The eradication of risk factor and the treatment of the secondary diseases plays the most important role in this disease stage without symptoms. A specific vessel training is indicated during stage II to encourage the development of collateral blood flow. Additionally, an interventional diagnostic and therapy should be considered in this stage with limitations in the daily activities. The administration of vasoactive drugs is controversly discussed. The acetylsalicylic acid (ASA) is remaining the most investigated substance for reducing the progress of the arteriosclerotic process. The administration of ticlopidine is justified in cases of ASA-allergies. The stages III and IV are characterized by pain at rest and necrosis. Firstly, the indication for a transcutaneous transluminal angioplasty, thrombolysis or bypass-surgery should be proofed. If procedures of revascularization are not possible, prostaglandines may improve the pain at rest and wound healing. Beside the stage of the occlusive vascular disease, the presence of risk factors, the physical status of the patient, and the location of the occlusion are of great importance for the decision about the treatment procedure.

Adult↗

PubMed1985

Carbamoylation of glutathione reductase and changes in cellular and chromosome morphology in a rat cell line resistant to nitrogen mustards but collaterally sensitive to nitrosoureas.

A Walker 256 rat carcinoma cell line (WR) with acquired resistance to nitrogen mustards has been found to lack cross-resistance to nitrosoureas. Although total cellular glutathione pools were similar in the parent (WS) and resistant cell lines (WS, 2.5 X 10(-6); WR, 2.0 X 10(-6) mol/mg protein), glutathione reductase activity was 3.98 in WR compared to 8.67 nmol reduced nicotinamide adenine dinucleotide phosphate oxidized per microgram protein per min in WS cells. Treatment of cells with a carbamoylating nitrosourea, N,N'-bis(trans-4-hydroxycyclohexyl)-N'-nitrosourea, produced a dose-dependent inhibition of glutathione reductase and depletion of thiols in both cell lines. The drug caused no direct DNA strand breakage, but a differential mitotic spindle-chromosome stain showed that spindle formation was inhibited in WR cells at N,N'-bis(trans-4-hydroxycyclohexyl)-N'-nitrosourea concentrations of greater than 50 microM. In WS cells, mitotic figures were still visible at 100 microM. Chromosomal damage was expressed in both cell lines at concentrations of 25 microM. The number and extent of these aberrations were greater in WR than WS. Observed karyotypic abnormalities included polyploidy, chromosome decondensation, and endoreduplication. In interphase cells, transmission electron microscopy showed that the most prevalent drug-induced lesions included (a) disappearance of plasma membrane filopodia, (b) appearance of membrane blebbing, and (c) development of irregular crescent-shaped nuclei. These morphological and cytogenetic changes correlate with cytotoxic responses of these cell lines to N,N'-bis(trans-4-hydroxycyclohexyl)-N'-nitrosourea and would be consistent with drug-induced inhibition of glutathione reductase.

Animals↗

PubMed1985

Spectral analysis of hippocampal EEG in the freely moving rat: effects of centrally active drugs and relations to evoked potentials.

Hippocampal EEG signals derived from chronically implanted electrodes in the freely moving rat were recorded before and after administration of centrally acting drugs, and analyzed by power and coherence spectra. Eserine, ether or urethane induced a low frequency (3-6 c/sec) theta power and coherence peak in the immobile rat, which was sensitive to atropine or scopolamine. After phencyclidine, theta that occurred during walking (7-8 c/sec) was virtually abolished by atropine while in the normal rat, absolute theta power was not affected by atropine. The residue spectrum, defined as the EEG spectrum with the theta harmonics removed, was sensitive to centrally acting drugs. Ether, urethane and pentobarbital suppressed fast waves of 50-100 c/sec, and under some conditions, enhanced 15-50 c/sec waves. Eserine enhanced (30-60 c/sec) fast waves during walking while atropine suppressed fast waves and increased irregular slow activity (less than 30 c/sec). The main effects of drugs and behavior on the residue spectra and on the average evoked potentials following stimulation of the Schaffer collaterals could be explained by a previously proposed model (Leung 1982) which suggests a continuum of hippocampal 'activation' (tonic input) under the various conditions.

Anesthetics↗

PubMed2006

Acquired resistance to chloroquine in human CEM T cells is mediated by multidrug resistance-associated protein 1 and provokes high levels of cross-resistance to glucocorticoids.

OBJECTIVE: To explore the onset and molecular mechanism of resistance to the antimalarial disease-modifying antirheumatic drug (DMARD) chloroquine (CQ) in human CEM T cells. METHODS: Human CEM cells were used as an in vitro model system to study the development of CQ resistance by growing cells in stepwise increasing concentrations of CQ. RESULTS: Over a period of 6 months, CEM cell lines developed 4-5-fold resistance to CQ. CQ resistance was associated with the specific overexpression of multidrug resistance-associated protein 1 (MRP-1), an ATP-driven drug efflux pump. This was illustrated by 1) overexpression of MRP-1 by Western blotting and 2) the complete reversal of CQ resistance by the MRP-1 transport inhibitors MK571 and probenecid. Importantly, CQ-resistant CEM cells retained full sensitivity to other DMARDs, including methotrexate, leflunomide, cyclosporin A, and sulfasalazine, but exhibited a high level of cross-resistance (>1,000-fold) to the glucocorticoid dexamethasone. The mechanistic basis for the latter was associated with aberrant signaling via the cAMP-protein kinase A pathway, since the cAMP-inducing agent forskolin reversed dexamethasone resistance. Finally, CQ-resistant CEM cells displayed a markedly reduced capacity to release proinflammatory cytokines (tumor necrosis factor alpha) and chemokines (interleukin-8). CONCLUSION: Induction of overexpression of the multidrug resistance efflux transporter MRP-1 can emerge after long-term exposure to CQ and results in CQ resistance and collateral resistance to dexamethasone. These findings warrant further detailed investigations into the possible role of MRP-1 and other members of the superfamily of drug efflux pumps in diminishing the efficacy of DMARDs in rheumatoid arthritis treatment.

Antirheumatic Agents↗

PubMed1993

Acetylcholine mimics ischemic preconditioning via a glibenclamide-sensitive mechanism in dogs.

The major objectives of the present study were to examine the ability of acetylcholine (ACh) to mimic ischemic preconditioning in dogs and to determine the role of cardiac ATP-sensitive potassium (KATP) channels in mediating its effects. Barbital-anesthetized open-chest dogs were subjected to 60 min of left anterior descending coronary artery (LAD) occlusion followed by 4 h of reperfusion. Preconditioning was elicited by 10 min of LAD occlusion followed by 10 min of reperfusion before the 60-min occlusion period. ACh (10 micrograms/min) or an equivalent volume of saline were infused into the LAD for 10 min followed by a 10-min drug-free period before the 60-min ischemic insult. In another group, the specific KATP channel blocker glibenclamide (0.3 mg/kg iv) was given 15 min before ACh administration. Transmural myocardial blood flow was measured at 30 min of occlusion, and infarct size (IS) was determined by triphenyltetrazolium staining and expressed as a percentage of the anatomic area at risk (AAR). There were no significant differences in hemodynamics, collateral blood flow, or AAR between groups. Preconditioning produced a marked reduction (P < 0.05) in IS (5.3 +/- 3.0 vs. 23.7 +/- 5.9% in the controls). ACh, similar to preconditioning, resulted in a dramatic decrease in IS (10.0 +/- 2.9%), whereas glibenclamide completely abolished its protective effects (20.9 +/- 4.8%). These results are the first to indicate that ACh mimics ischemic preconditioning via a cardiac KATP channel-sensitive mechanism in dogs.

Acetylcholine↗